Current Cancer Therapy Reviews - Volume 9, Issue 4, 2013

Spontaneous autoantibody responses against tumor-associated antigens have been detected in all types of cancer analyzed so far. Recent studies have shown that cancer-associated autoantibodies can be found in the serum of patients even several years before the clinical diagnosis. Furthermore, they may at least partially reflect the antigenic profile of cancer and the balance of immune cell subsets in the tumor microenvironment. Therefore, cancer associatedautoantibodies represent attractive biomarkers for the development of non-invasive serological tests for the diagnosis or early detection of cancer, prognosis of survival and prediction of the clinical benefit of immunotherapy. Still, the frequency of responses against each particular antigen is generally low and the autoantibody repertoire is highly heterogeneous and overlapping with that elicited by viral infections and autoimmune disorders, hence precluding the clinical use of single autoantibody biomarkers. This can, however, be overcome by analyzing the autoantibody responses to multiple antigens simultaneously. In this review, we discuss the diagnostic relevance of the recently identified cancer-associated autoantibody signatures and the challenges in the development of clinically applicable biomarker assays. In addition, the putative functional role and the significance of IgG subclasses in the anti-tumor immune response and their prognostic value are discussed.

The literature concerning the design of large-scale high-throughput multiplexed genotyping assays for profiling tumour somatic mutations, and studies of their validation and prospective clinical use in guiding targeted therapies, is reviewed. Reports of the design and development of genotyping approaches for the simultaneous detection of numerous oncogenic driver mutations in many known cancer genes first appeared in the literature between 2007 and 2010. Retrospective studies of the detection of somatic mutations in a representative series of human tumour specimens has provided evidence of analytical validity as well as technical accuracy and reliability. Six prospective clinical studies reported since 2011 have generated evidence supporting the clinical validity of these genotyping approaches in identifying tumour somatic mutations in cancer patients in a way that could guide their treatment options. Currently, over forty different targeted drug therapies are approved for clinical use in treating cancer that therapeutically address over sixty different cancer- associated genes and hundreds of individual oncogenic driver mutations. This expanding list of targetable cancer genes and driver mutations are now candidates for inclusion in customised genotyping designs for future clinical evaluation in guiding targeted cancer therapy.

Chronic lymphocytic leukemia (CLL) is a clonal lymphoid disease characterized by the proliferation and accumulation of small CD5/CD19/CD23-positive lymphocytes in the blood, lymph nodes, spleen, liver and bone morrow. The management of CLL is determined by the stage and activity of the disease, age and comorbidities. Currently available therapies are only partially efficient, exposing an obvious need to develop better strategies and new, more specific and active drugs. Recently, several new agents have been explored and have shown promise in treating CLL. New mAbs directed against CD20 include veltuzumab (IMMU-106) and obnutuzumab (GA-101), a novel third-generation fully humanized and optimized mAb. Monoclonal antibodies with another target than CD20 can be useful in the treatment of this disease. These treatments include anti-CD37 antibodies (Otlertuzumab and BI 836826) and anti-CD19 mAb (XmAb5574, MEDI-551, hBU12-vcMMAE). Recently, several small molecular kinase inhibitors, including spleen tyrosine kinase inhibitor and Bruton’s tyrosine kinase inhibitors, have been developed to target the proximal B-cell receptor (BCR) signaling pathway. These drugs are part of a promising new strategy for targeted treatment of CLL and are currently undergoing clinical development. The most advanced Bruton’s tyrosine kinase inhibitor in clinical trials is ibrutinib (PCI-32765). Ibrutinib is clinically active in patients with CLL, including high-risk CLL. The oral PI3K p110δ-selective inhibitor idelalisib (CAL-101) also shows preclinical and clinical activity against CLL. Moreover, lenalidomide and bcl-2 inhibitors demonstrate efficacy in CLL in preclinical studies and early clinical trials.

The presence of small amounts of circulating DNA in plasma was demonstrated 60 years ago. Since then, cellfree DNA has been tested for quantity, fragmentation pattern and tumor-specific sequences in patients with various malignancies. The introduction of improved detection methods showed that all these alterations are regularly detectable in many cancer patients and the investigation of cell-free DNA may provide useful diagnostic and prognostic information. Herein, we review the recent findings on cell-free DNA alterations in patients with prostate cancer and discuss its diagnostic and prognostic potential.

The post genome era has ushered us into therapeutic target discovery empowering us to mine the genome using rational approaches. Numerous cancer targets have emerged from the genome project for diagnostics, therapeutics and response to therapy prediction. Among thousands of genes predicted in the human genome, nearly half of them remain uncharacterized. Considerable attention in the last decade has focused on the well-characterized known genes. However, the future of cancer target discovery resides in the uncharacterized or novel genes called the dark matter of the human genome. Realizing the importance of this vast untapped potential, recently the US National Cancer Institute announced a new initiative called "Illuminating the Dark Matter of the Genome for Druggability". This area of cancer research albeit exciting, remains a challenge due to the lack of adequate information about the uncharacterized genes. Amongst the plethora of bioinformatics tools and databases, a streamlined approach remains elusive. In this review, we present a simplified approach to mine directly the cancer proteome for rapid target discovery. Using such an approach, we have created a database of uncharacterized cancer genes and have shown the biomarker and drug target potential for an uncharacterized protein, C1ORF87, as a putative solid tumor target. In view of this protein's association with carcinomas, the C1ORF87 is termed as Carcinoma-Related EF-Hand (CREF) gene. The approaches discussed in this review should aid in lighting the dark matter of the human cancer proteome.

Adenocarcinoma of the pancreas is the fourth leading cause of cancer-related death in the United States. Therapeutic responsiveness of pancreatic cancer to surgery, chemotherapy, and radiation therapy is poor, resulting in a dismal 5-year survival of less than 3%. Point mutation of the K-ras oncogene is a common event in the early development of pancreatic cancer. Indeed, K-ras mutations occur in up to 95% of pancreatic cancers, with a resulting overall increase in production of reactive oxygen species (ROS) through the activation of NADPH oxidase (NOX). Specifically, the extracellular (non-mitochondrial) generation of superoxide (O2.-) from the NOX system results in cell growth and tumor progression. Extracellular superoxide dismutase (SOD3, EcSOD) is the only isoform of superoxide dismutase (SOD) expressed extracellularly. It modulates ROS by converting O2.- into hydrogen peroxide (H2O2). Antioxidant enzymes that scavenge specific ROS have inhibited the in vitro and in vivo growth of pancreatic cancer. It has been demonstrated that overexpression of EcSOD inhibits pancreatic cancer cell growth and intracellular signaling pathways. Therefore, we propose that strategies to scavenge non-mitochondrial-generated superoxide may prove beneficial in the treatment pancreatic cancer. This review will focus on the role of O2.- as a pro-tumorigenic signaling molecule, including its generation and hypothesized mechanism of action, as well as the role of EcSOD in inhibiting tumor growth and propagation, and its potential as a targeted pancreatic cancer therapy.